Investigation of 1, 3, 4 Oxadiazole Derivative in PTZ-Induced Neurodegeneration: A Simulation and Molecular Approach

Faheem, Muhammad; Althobaiti, Yusuf S.; Khan, Abdul Waheed; Ullah, Aman; Ali, Shirook M.; Ilyas, Umair

doi:10.2147/jir.s328609

Cited by 6 publications

(8 citation statements)

References 53 publications

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“…Over the 300 ns MD simulations in the Desmond software package [ 37 ], we can observe that 1 in cluster 4 conformation had stable binding with the protein. The ‘Simulation Interactions Diagram’ modular was used in statistical analysis [ 38 ].…”

Section: Resultsmentioning

confidence: 99%

Exploring new catechin derivatives as SARS-CoV-2 Mpro inhibitors from tea by molecular networking, surface plasma resonance, enzyme inhibition, induced fit docking, and metadynamics simulations

Yang¹,

Wang²,

Qi³

et al. 2022

Computers in Biology and Medicine

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Section: Resultsmentioning

confidence: 99%

Exploring new catechin derivatives as SARS-CoV-2 Mpro inhibitors from tea by molecular networking, surface plasma resonance, enzyme inhibition, induced fit docking, and metadynamics simulations

Yang¹,

Wang²,

Qi³

et al. 2022

Computers in Biology and Medicine

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“…Consequently, the deficit in antioxidant capability in the STZ-induced DN group stimulated free radicals to assault cell membranes, initiate lipid peroxidation, and augment the level of inflammatory nitric oxide, thus damaging the tissue as a consequence of neuropathy ( Hosseini and Abdollahi, 2013 ). The lipid peroxidation augmented by free radicals, which may be generated through glucose-auto-oxidation and protein-glycation ( Metz et al, 2003 ), results in disruption of the antioxidant defense system ( Faheem et al, 2021 ). The development of LPO and iNOS, which is especially associated with diminishing defensive endogenous antioxidants of the body and increasing ROS production, in turn induced inflammation in the spinal cord ( Hains and Waxman, 2006 ).…”

Section: Discussionmentioning

confidence: 99%

“…After exposure to an isotonic environment through the addition of NaCl, the system was made electrically stable by adding counter ions, a Nose–Hoover thermostat maintaining a 300-k temperature, and pressure of 1.01325 bars by Martyna–Tobias–Klien barostate with 100 ns as the time of the simulations. Determination of electrostatic interactions was performed using the Mesh Ewald method ( Faheem et al, 2021 ).…”

Section: Methodsmentioning

confidence: 99%

Investigation of Natural Compounds for Therapeutic Potential in Streptozotocin-induced Diabetic Neuroinflammation and Neuropathic Pain

Faheem

Khan²,

Shah³

et al. 2022

Front. Pharmacol.

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Diabetic neuropathy (DN) is a serious microvascular complication of diabetes mellitus (DM) that impacts the nervous system. Several risk factors are involved in the progression and maintenance of DN-associated pain, such as higher expression of various inflammatory mediators, e.g., tumor necrotic factor-alpha (TNF-α), nuclear factor-kappa B (NF-κB), and cyclo-oxygenase-2 (COX-2). The present research explores the neuroprotective potential of natural isolates, including berbamine, bergapten, and carveol, on the DM-induced neuroinflammation and neurodegeneration that cause neuropathic pain. The study utilized computerized techniques, including computational analysis (a docking assay and a molecular dynamic simulation) before moving to in vivo protocols. Diabetic neuropathy was induced by intraperitonial injection (IP) of streptozotocin (65 mg/kg), and the animal subjects (rats) were kept for 4 weeks for the development of DN. Once diabetic neuropathy was confirmed, the subjects were treated with berbamine, bergapten, and carveol until the sixth week (i.e., 2 weeks of treatment). At the sixth week, the rats were sacrificed, and the sciatic nerve and spinal cord of each was collected for further molecular investigation. Docking and a molecular dynamic simulation (MDS) delivered the information that the natural compounds (berbamine, bergapten, and carveol) were interacting with the selected target protein (i.e., mitogen-activated protein kinase). After IP, it was found that berbamine, bergapten, and carveol had ameliorated mechanical allodynia and thermal hyperalgesia by the 28th day of the study (2 weeks after treatment) without affecting blood glucose levels. Berbamine, bergapten, and carveol markedly elevated the levels of glutathione (GSH) and glutathione s-transferase (GST), in both the sciatic nerve and spinal cord, and also reduced lipid peroxidase (LPO) and nitric oxide (NO). The abovementioned natural isolates reduced pathologic alterations provoked through DN, a finding confirmed through histopathological assays (hematoxylin and eosin staining and immuno-histochemical analysis). Treatment down regulated higher expressions of the inflammatory mediatorcyclooxygenase-2 (COX-2), tumor necrosis factor-α (TNF-α), and nuclear factor kappa B (NF-κB), as confirmed by ELISA and polymerase chain reaction (PCR). The outcomes of berbamine, bergapten, and carveol are compared with those of pregabalin as a positive control group. Compared to pregabalin, treatment with the aforementioned three natural compounds improved nociception and reduced hyperalgesic effects, and consequently reduced pain perception and inflammation. Our results suggest the mechanism for the neuro-protective impact of berbamine, bergapten, and carveol might possibly be arbitrated via COX-2, TNF-α, and NF-κB, and regulated by mitogen-activated protein kinase, ultimately ameliorating STZ-provoked, DM-induced neuroinflammation and neurodegeneration, and associated neuropathic pain.

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“…DSV was used to clean up the structures. PyRx was used to dock molecules ( Faheem et al, 2021 ; Shams ul Hassan et al, 2021 ).…”

Section: Methodsmentioning

confidence: 99%

Pharmacological basis of bergapten in gastrointestinal diseases focusing on H+/K+ ATPase and voltage-gated calcium channel inhibition: A toxicological evaluation on vital organs

Aslam

Khan²,

Qazi³

et al. 2022

Front. Pharmacol.

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Aim and objectives: This study aimed to establish a pharmacological basis for evaluating the effects of bergapten (5-methoxypsoralen) in gastrointestinal diseases and assessment of its toxicological profile.Methods: The pharmacokinetic profile was evaluated using the SwissADME tool. AUTODOCK and PyRx were used for evaluating the binding affinities. The obtained results were further investigated for a post-dock analysis using Discovery Studio Visualizer 2016. The Desmond software package was used to conduct molecular dynamic simulations of best bound poses. Bergapten was further investigated for antidiarrheal, anti-secretory, charcoal meal transit time, anti-ulcer, anti-H. pylori activity.Results: Bergapten at a dose of 50, 100, and 200 mg/kg was proved effective in reducing diarrheal secretions, intestinal secretions, and distance moved by charcoal meal. Bergapten at the aforementioned doses acts as a gastroprotective agent in the ethanol-induced ulcer model that can be attributed to its effectiveness against H. pylori. Bergapten shows concentration-dependent relaxation of both spontaneous and K+ (80 mM)-induced contractions in the isolated rabbit jejunum model; the Ca2+ concentration–response curves (CRCs) were shifted to the right showing potentiating effect similar to papaverine. For molecular investigation, the H+/K+ ATPase inhibitory assay indicated inhibition of the pump comparable to omeprazole. Oxidative stress markers GST, GSH, and catalase showed increased expression, whereas the expression of LPO (lipid peroxidation) was reduced. Histopathological examination indicated marked improvement in cellular morphology. ELISA and western blot confirmed the reduction in inflammatory mediator expression. RT-PCR reduced the mRNA expression level of H+/K+ ATPase, confirming inhibition of the pump. The toxicological profile of bergapten was evaluated by an acute toxicity assay and evaluated for behavioral analysis, and the vital organs were used to analyze biochemical, hematological, and histopathological examination.Conclusion: Bergapten at the tested doses proved to be an antioxidant, anti-inflammatory, anti-ulcer, and antidiarrheal agent and relatively safe in acute toxicity assay.

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Investigation of 1, 3, 4 Oxadiazole Derivative in PTZ-Induced Neurodegeneration: A Simulation and Molecular Approach

Cited by 6 publications

References 53 publications

Exploring new catechin derivatives as SARS-CoV-2 Mpro inhibitors from tea by molecular networking, surface plasma resonance, enzyme inhibition, induced fit docking, and metadynamics simulations

Exploring new catechin derivatives as SARS-CoV-2 Mpro inhibitors from tea by molecular networking, surface plasma resonance, enzyme inhibition, induced fit docking, and metadynamics simulations

Investigation of Natural Compounds for Therapeutic Potential in Streptozotocin-induced Diabetic Neuroinflammation and Neuropathic Pain

Pharmacological basis of bergapten in gastrointestinal diseases focusing on H+/K+ ATPase and voltage-gated calcium channel inhibition: A toxicological evaluation on vital organs

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